Fibroblast cells are particularly important in the wound healing process and in the aging of the skin. Hyperplasia and proliferation of soft tissue fibroblasts are vital to normal healing mechanisms. However, in some cases, an exaggerated healing response can result in the production of copious amounts of healing tissue (ground substance), also termed scar tissue. For example, various traumatic incidents, such as bums, surgery, infection and wounds are often characterized by the erratic accumulation of fibrous tissue rich in collagen and having increased proteoglycan ("PG") content. In addition to the replacement of normal tissue which has been damaged or destroyed, excessive and disfiguring deposits of collagen and new tissue sometimes form during the healing process. The excess collagen deposition has been attributed to a disturbance in the balance between matrix synthesis and matrix degradation, resulting from increased fibroblast metabolism and proliferation. Thus, therapies inhibiting fibroblast metabolism and proliferation, deposition of collagen, and formation of new tissue resulting therefrom, would be useful for treating scar tissue formation.
Surgical adhesions are attachments of organs or tissues to each other through scar tissue formation; such adhesions can cause severe clinical problems. The formation of some scar tissue after surgery or tissue injury is normal. In some cases, however, the scar tissue overgrows the region of injury and creates surgical adhesions, which tend to restrict the normal mobility and function of affected body parts. In particular, fibroblast proliferation and matrix synthesis is increased locally following such soft tissue injury. Adhesions then form when the body attempts to repair tissue by inducing a healing response. For example, this healing process can occur between two or more otherwise healthy separate structures (such as between loops of bowel following abdominal surgery). Alternately, following local trauma to a peripheral nerve, fibrous adhesions can form, resulting in severe pain during normal movement. Current measures for treating adhesions include localized surgical implants containing an amount of a compound that must remain present at the wound site to provide scar-reducing benefit. However, implants may induce a foreign body reaction in the host subject, and predispose the implantation site to infection. Thus, it would be beneficial to systemically administer a scar-reducing composition since this would allow greater control with respect to dosage and frequency of administration, and is non-invasive.
Keloids are tumors of connective tissue consisting of hyperplastic masses which occur in the dermis and adjacent subcutaneous tissue, most commonly following trauma, in certain susceptible individuals. Keloid lesions are formed when local skin fibroblasts undergo vigorous hyperplasia and proliferation in response to local stimuli. Known therapies for keloids, such as local injections of corticosteroids, have had only limited success, and scarring frequently recurs after a keloid is surgically removed. It would be beneficial for a patient to receive less invasive treatment of keloids, and to avoid scarring.
Hypertrophic scars are masses which can result from bums or other injuries to the skin. Such scars are usually permanent and resistant to known methods of therapy. It would be beneficial to have a method for successfully treating hypertrophic scars.
Depressed scars resulting from an inflammatory episode are characterized by contractions of the skin, and leave a cosmetically displeasing and permanent scar. The most common example is scarring which occurs following inflammatory acne. The depression occurs as a normal consequence of wound healing, and the scar tissue causing the depression is predominantly comprised of collagen resulting from fibroblast proliferation and metabolism. Some acne patients are successfully treated using steroids injected intralesionally, topical liquid nitrogen applications, or dermabrasion. In many cases, however, there is either no improvement or the treatment results in other complications. Additional disfiguring conditions of the skin, such as wrinkling, cellulite formation and neoplastic fibrosis also appear to result from excessive collagen deposition, which produces unwanted binding and distortion of normal tissue architecture. Collagenase, an enzyme which degrades collagen, has been injected intralesionally to reduce scarring in these conditions. However, multiple disfigurements may arise, which make local treatments difficult or impossible. Thus, it would be beneficial to provide patients with systemic treatments that could target conditions that are diffuse or not localized.
Proper wound healing generally requires restoration of the integrity of skin, tissue, or organ by use of sutures, staples and/or various adhesive closures. To promote wound healing, topical preparations of oil soluble vitamins such as Vitamin A, D, and E have been applied, but the efficacy of these treatments has not been established by controlled clinical studies.
Other treatments exist to promote wound healing and thereby decrease scarring through anti-fibrotic activity (i.e., by having an inhibitory effect upon fibrosis), including administration of collagenase, para-amino benzoic acid, dextran sulfate, and cross-linked hyaluronic acid. U.S. Pat. No. 5,731,298 describes a pharmaceutical composition for non-topical wound, scar and keloid treatment which contains cross-linked glycosaminoglycans. However, the pharmaceutical composition is administered intralesionally, i.e., by injection into the site where scar-reducing activity is desired. U.S. Pat. No. 4,524,065 describes a method in which collagenase is injected intralesionally to cleave bonds in the collagen structure comprising the scar, thereby permitting other enzymes to act on the resulting molecular fragments and reduce the scar tissue. U.S. Pat. No. 5,705,177 describes a method of using anionic polymers such as dextran sulfate and pentosan polysulfate to inhibit fibrosis, scar formation, and surgical adhesions. This method is even more invasive than those described above since it requires implantation of a surgical graft that has been treated with the antifibrotic compounds.
Thus, many problems are associated with known treatments for scar tissue. Most treatments require invasive techniques, such as injection, or implantation of a surgical device that releases an antifibrotic compound. Topical administration is less invasive, but requires monitoring since the topical preparation may be accidentally rubbed off or absorbed by a bandage. Furthermore, topical preparations do not reduce scarring beneath the skin, and are therefore ineffective against adhesions. Also, it is difficult to control the tissue concentration and penetration of locally applied drugs.
Known preventative measures generally require a physician to administer the relevant drug to the site of a surgical wound or lesion (e.g., by injection or surgical implant), usually at the time that such wound or lesion would occur. Thus, there is a need for an effective preventive treatment against scarring, and fibrosis generally, that involves less invasive means, and permits more certainty as to the amount of active ingredient reaching the site of the wound or lesion.
In addition, known methods of treatment require that the active ingredient remain at the site of administration for a sufficient time to be effective. But this often does not occur and several invasive administrations are required. Thus, it would be beneficial for the level of active ingredient to be maintained at the site of treatment without additional local administrations.
Also, stiff joints are caused by capsular contractures, adhesive capsulitis, and arthrofibrosis, which result from musculoskeletal surgery. Such stiff joints (e.g., knees, shoulders, elbows, ankles, and hips) inevitably cause abnormally high forces to be transmitted to the articular cartilage of the affected area. Over time, these forces result in the development of degenerative joint disease and arthritis. All of these conditions occur as a result of increased fibroblast matrix synthesis and resultant scar formation. For example, in arthrofibrosis and capsular contracture, fibroblasts form excessive amounts of matrix in response to local trauma, such as joint dislocation. In adhesive capsulitis (frozen shoulder), an excessive inflammatory response results in the unfettered production of cytokines and growth factors. This results in a scarred contracted shoulder capsule and causes joint stiffness.
There is a need in the art for a method of treating conditions such as these that are caused by scar formation.